Substituted benzazepinones

ABSTRACT

The invention relates to substituted 3-amino-1-arylalkyl-benzazepin-2-ones of the general formula ##STR1## wherein the substituents are defined in the specification; or salts thereof; to processes for the preparation thereof; and to the use thereof as well as to pharmaceutical compositions that comprise compounds of formula (I) or pharmaceutically acceptable salts thereof.

This application is the United States National phase of InternationalApplication Ser. No. PCT/EP93/03425, filed 6 Dec. 1993.

The invention relates to substituted3-amino-1-arylalkylbenzazepin-2-ones of the general formula ##STR2##wherein Ar is aryl;

X is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, lower alkyl, aryl-lower alkyl or acyl;

R₂ is lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,aryl-lower alkoxy-lower alkyl, aryl-lower alkyl or C₃ -C₇cycloalkyl-lower alkyl;

R₃ is carboxy; 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ ; loweralkoxycarbonyl; lower alkoxy-lower alkoxycarbonyl; aryl-loweralkoxycarbonyl; aryloxycarbonyl; carbamoyl; carbamoyl that (i) ismonosubstituted by hydroxy, lower alkanesulfonyl, halo-loweralkanesulfonyl or by arylsulfonyl, (ii) is monosubstituted ordisubstituted, the substituents being independent of one another, bylower alkyl, lower alkenyl, lower alkynyl or by phenyl-lower alkyl or(iii) is disubstituted by lower alkylene or by lower alkylene-X₁ -loweralkylene, X₁ being O, S or NH;

the ring A is unsubstituted or mono- or poly-substituted by substituentsselected from the group consisting of: lower alkyl, aryl-lower alkyl,lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,aryl-lower alkoxy, C₃ -C₇ -cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl,nitro, halogen, trifluoromethyl, amino and amino that is monosubstitutedor disubstituted, the substituents being independent of one another, bylower alkyl, aryl-lower alkyl or by aryl, or disubstituted by loweralkylene or by lower alkyleneoxy-lower alkylene;

or salts thereof; to processes for the preparation thereof; and to theuse thereof as well as to pharmaceutical compositions that comprisecompounds of formula (I) or pharmaceutically acceptable salts thereof.

Lactams of the benzazepin-2-one type are described, for example, in U.S.Pat. No. 4,477,464. Those compounds have an acyl-alkyl radical at the1-N atom of the heterocycle and may be used as ACE inhibitors in thetreatment of cardiovascular disorders.

Benzo-fused lactams of the type of compounds of formula I describedabove are disclosed in U.S. Pat. No. 4,692,522. In the compoundsspecified therein, the 1-N-atom has a substituent that is in turnsubstituted by an acyl radical, while the N-atom bonded at the3-position of the heterocycle in such a constellation may be bothN-acylated and N-alkylated. Also specified are those compounds that aresubstituted at the 1-N-atom of the heterocycle by a non-acylatedradical, the amino group bonded at the 3-position of the heterocyclebeing N-acylated only. Compounds of that substance class may be used ascholecystokinin antagonists.

In contrast, the compounds of the present invention, in which the1-N-atom of the benzazepinone ring has a non-acylated hydrocarbonradical and in which the amino group bonded in the 3-position of thering is N-alkylated, have a different spectrum of activity.

There are described in the literature two receptor sub-types AT₁ and AT₂! of angiotensin(II) which differ in respect of their differentaffinities for synthetic angiotensin-II analogues.

AT₂ -receptors can be identified in various body tissues. Such receptorsare described in the relevant literature as being expressed, forexample, in neuron tumour cells, in transformed neural cells, in variousregions of the central nervous system, in the heart and the arteries, infemale reproductive organs, such as the uterus and the ovaries, in theadrenal glands and the pancreas and also in healing skin.

Surprisingly, the compounds of the present invention exhibit selectivebinding to the angiotensin-II-AT₂ -receptor in the model described byWhitebread et al., Biochem. Biophys. Res. Comm. 1989; 163, 184-191.Those binding properties of the compounds according to the inventionwere detected below a concentration of 50 μmol/l. Accordingly, thecompounds according to the invention may be used especially in theprophylactic or therapeutic treatment of symptoms that are caused by AT₂-receptors.

It has been demonstrated that an AT₂ -receptor stimulation

modulates the protein tyrosine phosphatase in the rat phaeochromocytomacell line PC12W and in AT₂ -receptor transfected COS cells Botari etal., Biochem. Biophys. Res. Commun. 1992, 183, 206-211: Botari et al.,Front. Neuroendocrinol. 1993, 44, 207-213; Brechler et al., Regul.Peptide 1993, 44, 207-213; Kambayashi et al., J. Biol. Chem. 1993, 268,24543-24546!

inhibits the guanylate cyclase in PC12W and neuron cultures Botari etal., Biochem. Biophys. Res. Commun. 1992, 183, 206-211; Botari et al.,Front. Neuroendocrinol. 1993, 44, 207-213; Brechler et al., Regul.Peptide 1993, 44, 207-213; Summers et al., Am. J. Physiol. 1991, 260,679-687; Summers et al., Proc. Natl. Acad. Sci. USA 1991, 88, 7567-7571!and

modulates T-type Ca⁺⁺ flows in neuroblastoma NG108-15 cells Buinon etal., FEBS 1992, 309, 161-164!. In addition, the AT₂ -receptor isinvolved in cell growth and cell proliferation, since it is especiallyexpressed in high density during foetal development Grady et al., J.Clin. Invest. 1991, 88 921-933!.

As a result of the ability of AT₂ -ligands to inhibit the proliferationof vascular endothelial cells, and since endothelial cell proliferationis the cause of angiogenesis, which is in turn a prerequisite for tumourgrowth and the development of metastases, the compounds according to theinvention may be used in the treatment of cancer and those disordersgenerally associated with benign and malignant proliferation.

AT₂ -receptors also bring about the modulation of phosphotyrosinephosphatase activity (PTPase activity), which is associated withgrowth-inhibiting and antiproliferative effects. AT₂ -receptors areexpressed in vascular smooth muscle cells during neointimal development.The compounds according to the invention may therefore be used in thetreatment of vascular proliferation disorders, including vascular cellwall hypertrophy, which follows a thrombosis, angioplasty, Buerger'sdisease, atherosclerosis and arteriosclerosis.

The modulation of PTPase activity also plays a part in connection withthe action of insulin, which is mediated by a tyrosine kinase receptorand a signal pathway for the tyrosine-phosphorylation/dephosphorylationenzyme system. Accordingly, the compounds according to the invention mayalso be used in the treatment of diabetic disorders and complications,including diabetic neuropathy, nephropathy and vasculopathy.

AT₂ -receptors also regulate the diameter of cerebral arteries and thuscerebral blood flow, and are thus suitable for the treatment of cerebralischaemia and strokes and associated symptoms.

A further important field of treatment arises from the fact that AT₂-receptors are localised in selective areas of the brain that areassociated with the control of motor activity, of sensory and visualphenomena and of the limbic system, and with the regulation of appetite.Similarly, calcium flows, which are associated with the control ofneurosecretion and electrical activity, are modulated by AT₂ -receptors.Accordingly, the compounds according to the invention may be used in thetreatment and diagnosis of numerous neurological, psychiatric,neuroendocrinal, neurodegenerative and neuroimmunological disorders,including disorders associated with dependency, anxiety states,depression, epilepsy, memory, psychoses, pain, sleep, tardivedyskinesia, hyperactivity and Petit Mal, and disorders associated withthe regulation of autonomous functions, and also in the treatment ofParkinson's disease, Alzheimer's disease and appetite disorders andassociated phenomena, such as obesity and anorexia.

Since, as mentioned, AT₂ -receptors influence PTPase activity, and suchreceptors have also been identified in healing skin, the compoundsaccording to the invention can also modulate cell growth and thedifferentiation of the skin and play a part in the reorganisation ofskin tissue, thereby promoting the healing of wounds and preventingkeloid formation.

AT₂ -receptors that exert a regulatory effect on ovulation have alsobeen found in ovarian follicle cells. To that extent the compoundsaccording to the invention may be used to treat sterility that has beencaused by anovulation, ovulation disorders, dysfunction of the corpusluteum, missed abortion and also other such disorders that areassociated with ovary dysfunction, including premenstrual syndrome anddysmenorrhoea.

There is a high density of AT₂ -receptors in the human myometrium. As aresult of the stimulation of PTPase activity, contraction of the uteruscan be inhibited, and the compounds according to the invention may beused in the treatment of disorders caused by abnormal uteruscontraction, including dysmenorrhoea, missed abortion, hypertrophy andhyperkinesia.

Similarly, PTPase activity can also modulate the activity of tyrosinekinase and other enzymes associated with cell proliferation and celldifferentiation, as a result of which the compounds according to theinvention may also be used in the treatment and prophylaxis of fibromasof the uterus.

AT₂ -receptors play a part in the regulation of cardiac function. Thedemonstrated effect of AT₂ -receptors on T-type calcium flow may play animportant part in the heart in arrhythmogenesis and in the modulation ofpace-maker function in the sinoauricular node. Accordingly, thecompounds of the present invention may be used in the treatment ofcardiac insufficiency and arrhythmia. They are furthermore useful in thetreatment of cardiac hypertrophy, since AT₂ -receptors cause an increasein PTPase activity, which is generally to be regarded asgrowth-inhibiting.

AT₂ -receptors are furthermore found in the zona glomerulosa, zonafasciculata and medulla of the adrenal glands. Since T-type calciumflows are modulated and, furthermore, anti-proliferative properties areimparted by those receptors, the compounds according to the inventionmay be used in the treatment of hypertrophy and hypersecretion of theadrenal cortex, such as Cushing's syndrome, adrogenital syndrome andprimary hyperaldosteronism.

The modulation of T-type calcium flows enables the compounds accordingto the invention to be used in the treatment of disorders involved withthe deregulation of the pancreas and exocrinal secretion, such aspancreatitis, hyperinsulinism and Zollinger-Ellison syndrome.

There is a special need for medicaments to be available for thetreatment of post myocardial infarction in order effectively to treatcardiac failure following a cardiac infarction. An appropriate therapyshould advantageously be undertaken after the repairing and healingphase of the heart. An acute myocardial infarction is known to causeboth a change in haemodynamic effects and an alteration in structure inthe damaged and healthy zones of the heart. Thus a myocardial infarctionreduces, for example, the maximum cardiac output and the stroke volume.Those haemodynamic effects can be ascertained in a manner known per so,for example in the rat model Schoemaker et al. J. Mol. Cell Cardiol. 23,187-197 (199)!. Also associated with myocardial infarction is astimulation of the DNA synthesis occurring in the interstice as well asan increase in the formation of collagen in the areas of the heart notaffected van Krimpen et al, J. Mol. Cell Cardiol. 23, 1245-1253 (1991)!.

Surprisingly, the compounds according to the invention and the saltsthereof reduce the DNA synthesis. Also, the post-myocardial treatmentcauses an improvement in the negative haemodynamic effects. Thoseregulatory effects are attributable to the binding of the compounds tothe AT₂ -receptor. These findings are obtained using the methodology,known per so, according to Schoemaker et al. J. Mol. Cell Cardiol. 23,187-197 (1991) and van Krimpen et al. J. Mol. Cell Cardiol. 23,1245-1253 (1991) and also Smits et al., Journal of CardiovascularPharmacology, 20: 772-778 (1992). In both techniques, a cardiacinfarction is induced in rats in the rat model, and the activeingredient is administered over weeks after the infarction, for exampleusing an osmotic minipump. The active ingredients are advantageouslyadministered from three to five weeks after the myocardial infarctionhas been induced, and the haemodynamic effects as well as the formationof the relevant DNA are ascertained. The results clearly show that onthe one hand the DNA synthesis is significantly reduced and on the otherhand the negative haemodynamic effects are normalised. Correspondinganimal experiment results with the ACE-inhibitor captopril, known to beused in the treatment of post myocardial infarction, could be confirmedwith captopril also in humans Pfeffer et al. N. Engl. J. Med. 1992, 327,669-677!.

Altogether, the compounds according to the invention and the saltsthereof are therefore distinguished by a favourable profile of activity.

Accordingly, the compounds of formula I and the pharmaceuticallyacceptable salts thereof may be used, for example, as active ingredientsthat are employed, for example, in the treatment of disorders caused bymodulation of the AT₂ -receptor, for example in the treatment ofdisorders of the kind described hereinbefore. The invention thus relatesto the use of compounds of formula I and pharmaceutically acceptablesalts thereof in the preparation of corresponding medicaments and in thetherapeutic treatment of disorders caused by modulation of the AT₂-receptor. Also included in the preparation of the medicaments is thecommercial presentation of the active substances.

The compounds of formula I may be in the form of salts, especiallypharmaceutically acceptable salts. If the compounds I have, for example,at least one basic centre, they can form acid addition salts. Thosesalts are formed, for example, with strong inorganic acids, such asmineral acids, e.g. sulfuric acid, a phosphoric acid or a hydrohalicacid, with strong organic carboxylic acids, such as unsubstituted orsubstituted, e.g. halosubstituted, C₁ -C₄ alkanecarboxylic acids, e.g.acetic acid, saturated or unsaturated dicarboxylic acids, e.g. oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid,hydroxycarboxylic acids, e.g. ascorbic, glycolic, lactic, malic,tartaric or citric acid, amino acids, e.g. aspartic or glutamic acid, orbenzoic acid, or with organic sulfonic acids, such as unsubstituted orsubstituted, e.g. halosubstituted, C₁ -C₄ alkane- or aryl-sulfonicacids, e.g. methane- or p-toluene-sulfonic acid. Corresponding acidaddition salts may also be formed with a basic centre optionally presentin addition. Also, compounds I having at least one acid group (e.g. COOHor 5-tetrazolyl) can form salts with bases. Suitable salts with basesare, for example, metal salts, such as alkali metal or alkaline earthmetal salts, e.g. sodium, potassium or magnesium salts, or salts withammonia or an organic amine, such as morpholine, thiomorpholine,piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, e.g.ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- ordimethyl-propyl-amine, or a mono-, di- or tri-hydroxy-lower alkylamine,e.g. mono-, di- or tri-ethanolamine. Furthermore, corresponding internalsalts may be formed. Also included are salts that are not suitable forpharmaceutical use, which are used, for example, for the isolation orpurification of free compounds I or pharmaceutically acceptable saltsthereof.

The compounds according to the invention have at least two opticallyactive carbon atoms and may accordingly be in the form of stereoisomersor mixtures of stereoisomers or in the form of pure enantiomers ordiastereoisomers. The present invention also includes correspondingstereoisomers.

Aryl and aryl in aryl-lower alkyl, aryl-lower alkoxycarbonyl oraryloxycarbonyl and also in aryl-lower alkanoyl, is preferablycarbocyclic aryl, such as phenyl or naphthyl, or heterocyclic aryl, suchas monocyclic monoaza-, monooxa-, monothia-, diaza-, oxaza- orthiaza-aryl, e.g. pyrrolyl, pyridyl, furyl, thienyl, imidazolyl,isoxazolyl, or thiazolyl. Such carbocyclic and heterocyclic arylradicals are, for example, independently of one another, unsubstitutedor mono- or poly-substituted, e.g. di- or tri-substituted, bysubstituents selected from the group consisting of: lower alkyl,aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, loweralkoxy-lower alkoxy, aryl-lower alkoxy, C₁ -C₇ -cycloalkyl, C₃ -C₇cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino and aminothat is mono-substituted or disubstituted, the substituents beingindependent of one another, by lower alkyl, aryl-lower alkyl or by aryl,or disubstituted by lower alkylene or by lower alkyleneoxy-loweralkylene. Preferred aryl is phenyl that is unsubstituted or mono- orpoly-substituted, e.g. di- or tri-substituted, in the manner indicatedhereinbefore.

Acyl is, for example, lower alkanoyl, aryl-lower alkanoyl, or aroyl,especially benzoyl, that may be unsubstituted or may be substituted asindicated hereinbefore for carbocyclic aryl.

The general terms used hereinbefore and hereinafter have the followingmeanings, unless specified to the contrary:

The term "lower" denotes that corresponding groups and compounds eachcontain especially up to and including 7, preferably up to and including4, carbon atoms.

Lower alkyl ist especially C₁ -C₇ alkyl, that is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or acorresponding pentyl, hexyl or heptyl radical. C₁ -C₄ -alkyl ispreferred.

Lower alkenyl is especially C₃ -C₇ alkenyl and is e.g. 2-propenyl or 1-,2- or 3-butenyl. C₃ -C₅ alkenyl is preferred.

Lower alkynyl is especially C₃ -C₇ alkynyl and is preferably propargyl.

Hydroxy-lower alkyl is especially hydroxy-C₁ -C₄ alkyl, such ashydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.

C₁ -C₂ alkylene is methylene or 1,1-ethylene or 1,2-ethylene.

C₃ -C₇ cycloalkyl is especially cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

C₃ -C₇ cycloalkyl-lower alkyl is especially C₃ -C₇ cycloalkyl-C₁ -C₇alkyl, such as cyclopropylmethyl, 2-cyclopropyl-ethyl,3-cyclopropyl-propyl, cyclopentyl-methyl, 2-cyclopentyl-ethyl,3-cyclopentyl-propyl, cyclohexylmethyl, 2-cyclohexyl-ethyl or3-cyclohexyl-propyl. C₅ -C₆ cycloalkyl-C₁ -C₄ alkyl, such ascyclohexylmethyl or 2-cyclohexyl-ethyl, is preferred.

Lower alkoxy is especially C₁ -C₇ alkoxy, that is methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy orcorresponding pentyloxy, hexyloxy or heptyloxy. C₁ -C₄ alkoxy ispreferred.

Lower alkoxy-lower alkyl is especially C₁ -C₄ alkoxy-C₁ -C₄ -alkyl, suchas 2-methoxyethyl, 2-ethoxyethyl, 2-(n-propoxy)-ethyl or ethoxymethyl.

Lower alkoxy-lower alkoxy is especially C₁ -C₄ alkoxy-C₁ -C₄ -alkoxy,such as methoxymethoxy, ethoxymethoxy, 2-methoxy-ethoxy or2-ethoxy-ethoxy.

Halogen is especially halogen having an atomic number of up to andincluding 35, that is fluorine, chlorine or bromine, and also includesiodine.

Lower alkylene is especially C₂ -C₇ alkylene, is straight-chain orbranched and is especially ethylene, 1,3-propylene, 1,4-butylene,1,2-propylene, 2-methyl-1,3-propylene or 2,2-dimethyl-1,3-propylene. C₂-C₅ alkylene is preferred.

Lower alkyleneoxy-lower alkylene is especially C₂ -C₄ alkyleneoxy-C₂ -C₄alkylene, preferably ethyleneoxyethylene.

Lower alkoxycarbonyl is especially C₂ -C₈ alkoxycarbonyl and is e.g.methoxy-, ethoxy-, propoxy- or pivaloyloxy-carbonyl. C₂ -C₅alkoxycarbonyl is preferred.

Lower alkoxy-lower alkoxycarbonyl is especially C₁ -C₄ alkoxy-C₁ -C₄alkoxycarbonyl, preferably ethoxy-ethoxycarbonyl, methoxyethoxycarbonylor isopropoxy-ethoxycarbonyl.

Naphthyl is especially 1- or 2-naphthyl. Pyrrolyl is especially 2- or3-pyrrolyl. Pyridyl is especially 2-, 3- or 4-pyridyl. Furyl isespecially 2- or 3-furyl. Thienyl is especially 2- or 3-thienyl.Imidazolyl is especially 2-, 4- or 5-imidazolyl. Isoxazolyl isespecially 3- or 4-isoxazolyl. Thiazolyl is especially 2-, 3- or5-thiazolyl.

Lower alkanoyl is especially C₁ -C₇ alkanoyl and is e.g. formyl, acetyl,propionyl, butyryl, isobutyryl or pivaloyl. C₂ -C₅ alkanoyl ispreferred.

Phenyl-lower alkanoyl is especially phenyl-C₂ -C₅ alkanoyl and is e.g.phenylacetyl, 3-phenylpropionyl or 4-phenylbutyryl.

Lower alkylamino is especially C₁ -C₇ alkylamino and is e.g. methyl-,ethyl-, n-propyl- or isopropyl-amino. C₁ -C₄ alkylamino is preferred.

Phenyl-lower alkylamino is preferably phenyl-C₁ -C₄ alkylamino,especially benzyl- or 1- or 2-phenylethyl-amino.

Di-lower alkylamino is especially di-C₁ -C₄ alkylamino, such asdimethyl-, diethyl-, di(n-propyl)-, methyl-propyl-, methyl-ethyl-,methyl-butyl- or dibutyl-amino.

N-lower alkyl-N-phenyl-lower alkyl-amino is especially N-C₁ -C₄alkyl-N-phenyl-C₁ -C₄ alkyl-amino, preferably methyl-benzyl-amino orethyl-benzyl-amino.

Di(phenyl-lower alkyl)amino is especially di(phenyl-C₁ -C₄ -alkyl)amino,preferably dibenzylamino.

Amino that is disubstituted by lower alkylene is especially C₂ -C₆alkyleneamino, preferably C₄ -C₆ alkyleneamino, such as 1-pyrrolidino or1-piperidino.

Amino that is disubstituted by lower alkyleneoxy-lower alkylene isespecially C₂ -C₄ alkyleneoxy-C₂ -C₄ alkyleneamino, preferably4-morpholino.

Halo-lower alkanesulfonyl is especially halo-C₁ -C₇ alkane-sulfonyl,such as chloromethane-, fluoro-dichloromethane-, trichloromethane- ortrifluoromethane-sulfonyl. Halo-C₁ -C₄ -alkanesulfonyl is preferred.

The invention relates especially to compounds of formula I wherein

Ar is aryl;

X is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, lower alkyl, aryl-lower alkyl or acyl;

R₂ is lower alkyl, aryl-lower alkyl or C₃ -C₇ cycloalkyl-lower alkyl;

R₃ is carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ ; the ring A isunsubstituted or mono- or poly-substituted by substituents selected fromthe group consisting of: lower alkyl, aryl-lower alkyl, loweralkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-loweralkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl, nitro,halogen, trifluoromethyl, amino and amino that is monosubstituted ordisubstituted, the substituents being independent of one another, bylower alkyl, aryl-lower alkyl or by aryl, or disubstituted by loweralkylene or by lower alkyleneoxy-lower alkylene;

or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl;

X is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, lower alkyl, lower alkyl that is substituted by phenyl,naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl orby thiazolyl, lower alkanoyl, lower alkanoyl that is substituted byphenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl,isoxazolyl or by thiazolyl, or benzoyl;

R₂ is (i) lower alkyl, lower alkyl that is substituted by phenyl,naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl orby thiazolyl, or C₃ -C₇ cycloalkyl-lower alkyl, or (ii) hydroxy-loweralkyl, lower alkoxy-lower alkyl, or lower alkoxy-lower alkyl in whichthe lower alkoxy moiety is substituted by phenyl, naphthyl, pyrrolyl,pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or by thiazolyl;

R₃ is (i) carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ or (ii) loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, phenyl-loweralkoxycarbonyl, benzoylcarbonyl, carbamoyl, lower alkylcarbamoyl,di-lower alkylcarbamoyl, phenyl-lower alkylcarbamoyl, diphenyl-loweralkylcarbamoyl, hydroxy-carbamoyl, lower alkanesulfonyl-carbamoyl,halo-lower alkanesulfonyl or phenylsulfonyl;

the ring A and carbocyclic and heterocyclic aromatic radicals are,independently of one another, unsubstituted or mono- or poly-substitutedby substituents selected from the group consisting of: lower alkyl,lower alkyl that is substituted by phenyl, naphthyl, pyrrolyl, pyridyl,furyl, thienyl, imidazolyl, isoxazolyl or by thiazolyl, loweralkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl,nitro, halogen, trifluoromethyl, amino and amino that is monosubstitutedor disubstituted, the substituents being independent of one another, bylower alkyl, phenyl-lower alkyl or by phenyl, or disubstituted by loweralkylene or by lower alkyleneoxy-lower alkylene;

stereoisomers or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl;

X is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl,phenyl-lower alkanoyl or benzoyl;

R₂ is lower alkyl, phenyl-lower alkyl or C₃ -C₇ cycloalkyl-lower alkyl;

R₃ is carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ or (ii) carbamoylor hydroxy-carbamoyl;

the ring A and carbocyclic and heterocyclic aromatic radicals are,independently of one another, unsubstituted or mono- or poly-substitutedby substituents selected from the group consisting of: lower alkyl,phenyl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, loweralkoxy-lower alkoxy, phenyl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino and aminothat is monosubstituted or disubstituted, the substituents beingindependent of one another, by lower alkyl, phenyl-lower alkyl or byphenyl, or disubstituted by lower alkylene or by lower alkyleneoxy-loweralkylene;

stereoisomers or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl or phenyl substituted by C₁ -C₄ alkyl;

X is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, C₁ -C₄ alkyl or C₂ -C₅ alkanoyl;

R₂ is phenyl-C₁ -C₄ alkyl or C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl;

R₃ is carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ ;

the ring A is unsubstituted or mono- or poly-substituted by substituentsselected from the group consisting of: C₁ -C₄ alkyl, halogen, C₁ -C₄alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkoxy-C₁ -C₄ alkoxy, nitro,halogen and trifluoromethyl;

stereoisomers or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl substituted by C₁ -C₄ alkyl, lower alkoxy, halogen,trifluoromethyl, amino, lower alkylamino, di-lower alkylamino or bynitro;

X is methylene;

R₁ is hydrogen or C₂ -C₅ alkanoyl;

R₂ is phenyl-C₁ -C₄ alkyl wherein phenyl is unsubstituted or issubstituted by halogen, trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄alkoxy; or R₂ is C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl;

R₃ is carboxy, carbamoyl or hydroxycarbamoyl;

the ring A is unsubstituted or mono- or poly-substituted by substituentsselected from the group consisting of: C₁ -C₄ -alkyl, halogen, C₁ -C₄alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkoxy-C₁ -C₄ alkoxy, nitro,halogen and trifluoromethyl;

stereoisomers or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl or phenyl substituted, especially in the para-position, byC₁ -C₄ alkyl, such as p-isopropylphenyl;

X is methylene;

R₁ is hydrogen or C₂ -C₅ alkanoyl;

R₂ is phenyl-C₁ -C₄ alkyl or C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl;

R₃ is carboxy or 5-tetrazolyl;

the ring A is unsubstituted or is mono- or poly-substituted bysubstituents selected from the group consisting of: C₁ -C₄ -alkyl,halogen, C₁ -C₄ alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ -alkoxy-C₁-C₄ alkoxy, nitro, halogen and trifluoromethyl;

stereoisomers or salts thereof.

The invention relates especially to compounds of formula (Ia) ##STR3##wherein R₁ is hydrogen;

R₂ is phenyl-C₁ -C₄ alkyl, such as 2-phenyl-ethyl, or C₃ -C₇cycloalkyl-C₁ -C₄ alkyl, such as 2-cyclohexyl-ethyl;

R₃ is carboxy; and

R₄ is C₁ -C₄ alkyl, especially isopropyl, that is bonded especially inthe para-position;

stereoisomers or salts thereof.

The invention relates especially to compounds of formula (Ib) ##STR4##wherein R₁ is hydrogen;

R₂ is phenyl-C₁ -C₄ alkyl, such as 2-phenyl-ethyl, or C₃ -C₇cycloalkyl-C₁ -C₄ alkyl, such as 2-cyclohexyl-ethyl;

R₃ is carboxy; and

R₄ is C₁ -C₄ alkyl, especially isopropyl;

stereoisomers or salts thereof.

The invention relates to compounds of formulae I, Ia and Ib wherein thecarbon atom having the variables R₂ and R₃ has the (S)-configuration.Preferred are compounds of formulae I, Ia and Ib wherein both the carbonatom having the variables R₂ and R₃, and the heterocycle carbon atom towhich the amino group is bonded, have the (S)-configuration.

The invention relates specifically to the novel compounds of formula Imentioned in the Examples and to the stereoisomers and salts thereof.

The invention relates furthermore to a process for the preparation ofcompounds of formula I and the stereoisomers and salts thereof, whichcomprises, for example,

a) in a compound of formula ##STR5## wherein X₁ is a radical that can beconverted into the variable R₃, or in a salt thereof, converting X₁ intothe variable R₃ ; or,

b) for the preparation of a compound of formula (I) wherein R₁ ishydrogen, or for the preparation of a salt thereof, in a compound offormula ##STR6## wherein X₂ is an amino-protecting group, or in a saltthereof, removing the amino-protecting group; or

c) reacting a compound of formula ##STR7## with a compound of formula##STR8## wherein X₅ is a nucleofugal leaving group, or with a compoundof formula R₂ --CO--R₃ (IVc) or a salt thereof; or

d) reacting a compound of formula ##STR9## with a compound of formula X₆--X--Ar (Vb), wherein X₆ is a nucleofugal leaving group, or with a saltthereof; or

e) reacting a compound of formula ##STR10## wherein X₇ is (i) oxo or(ii) reactive esterified hydroxy together with hydrogen, with a compoundof formula ##STR11## or with a salt thereof; and in each case, ifdesired, converting a compound of formula I obtainable according to theprocess or in some other manner, in each case in free form or salt form,into a different compound of formula I, separating a mixture of isomersobtainable according to the process and isolating the desired isomerand/or converting a free compound of formula I obtainable according tothe process into a salt or converting a salt of a compound of formula Iobtainable according to the process into the free compound of formula Ior into a different salt.

The reactions described in the variants hereinbefore and hereinafter arecarried out in a manner known per se, e.g. in the absence or customarilyin the presence of a suitable solvent or diluent or a mixture thereof,if required with cooling, at room temperature or with heating, e.g. in atemperature range of approximately from -80° C. to the boilingtemperature of the reaction medium, preferably from approximately -10°to approximately +200° C., and, if necessary, in a closed vessel, underpressure, in an inert gas atmosphere and/or under anhydrous conditions.

Details concerning corresponding procedures and reaction conditions maybe found especially also in the Examples.

Variant a)

A radical X₁ that can be converted into carboxy R₃ is, for example,functionally modified carboxy or a radical that can be convertedoxidatively into carboxy.

There comes into consideration as functionally modified carboxy, forexample, esterified carboxy different from R₃, amidated carboxy orcyano.

Esterified carboxy different from R₃ is, for example, carboxy esterifiedby an unsubstituted or substituted aliphatic, cycloaliphatic or aromaticalcohol. An aliphatic alcohol is, for example, a lower alkanol, such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol ortert-butanol, that is substituted by cyano or by a silyl radical, whilethere comes into consideration as a cycloaliphatic alcohol, for example,a 3- to 8-membered cycloalkanol, such as cyclo-pentanol, -hexanol or-heptanol. An aromatic alcohol is, for example, a phenol or aheterocyclic alcohol, each of which may be substituted, especiallyhydroxypyridine, e.g. 2-, 3- or 4-hydroxypyridine.

Amidated carboxy is, for example, carbamoyl, or carbamoyl that ismonosubstituted by hydroxy, amino or by unsubstituted or substitutedphenyl, mono- or di-substituted by lower alkyl, or disubstituted by 4-to 7-membered alkylene or by 3-aza-, 3-lower alkylaza-, 3-oxa- or3-thia-alkylene. There may be mentioned as examples carbamoyl, N-mono-or N,N-di-lower alkylcarbamoyl, such as N-methyl-, N-ethyl-,N,N-di-methyl-, N,N-diethyl- and N,N-dipropyl-carbamoyl, pyrrolidino-and piperidino-carbonyl, morpholino-, piperazino-, 4-methylpiperazino-and thiomorpholino-carbonyl, anilinocarbonyl and anilinocarbonylsubstituted by lower alkyl, lower alkoxy and/or by halogen.

Preferred functionally modified carboxy is, for example, cyano-loweralkoxycarbonyl, such as 2-cyanoethoxycarbonyl, silyloxy-carbonyl, suchas tri-lower alkylsilyloxycarbonyl, e.g. tri(m)ethylsilyloxycarbonyl,and cyano.

Preferred X₁ is, for example, cyano.

Compounds of formula I wherein R₃ is carboxy may be prepared, forexample, starting from compounds of formula II wherein X₁ is cyano,esterified carboxy different from R₃, or amidated carboxy, by means ofhydrolysis, especially in the presence of a base.

The following X₁ especially can be converted in a manner known per seinto carboxy R₃ : 2-cyanoethoxycarbonyl X₁ can be converted into carboxyR₃, for example, by means of hydrolysis in the presence of a base,2-trimethylsilyloxycarbonyl can be converted into carboxy R₃ bytreatment with a fluoride, such as an alkali metal fluoride, e.g. sodiumfluoride, and silyloxycarbonyl X₁ can be converted into carboxy R₃ bytreatment with an acid.

There come into consideration as bases, for example, alkali metalhydroxides, hydrides, amides, alkanolates, carbonates,triphenylmethylides, di-lower alkylamides, aminoalkylamides or loweralkylsilylamides, naphthaleneamines, lower alkylamines, basicheterocycles, ammonium hydroxides, as well as carbocyclic amines. Theremay be mentioned by way of example sodium hydroxide, hydride and amide,potassium tert-butanolate, potassium carbonate, lithiumtriphenylmethylide, lithium diisopropylamide, potassium3-(aminopropyl)-amide, potassium bis-(trimethylsilyl)-amide,dimethylaminonaphthalene, di- or tri-ethylamine, orethyl-diisopropylamine, N-methylpiperidine, pyridine,benzyltrimethylammonium hydroxide, 1,5-diazabicyclo 4.3.0!non-5-ene(DBN) and also 1,8-diaza-bicyclo 5.4.0!undec-7-ene (DBU).

There comes into consideration as an acid, for example, a stronginorganic acid, such as a mineral acid, e.g. sulfuric acid, a phosphoricacid or a hydrohalic acid, a strong organic carboxylic acid, such as anunsubstituted or substituted, e.g. halosubstituted, C₁ -C₄alkanecarboxylic acid, e.g. acetic or trifluoroacetic acid, or anorganic sulfonic acid, such as an unsubstituted or substituted, e.g.halosubstituted, C₁ -C₄ alkane- or aryl-sulfonic acid, e.g. methane- orp-toluene-sulfonic acid.

There comes into consideration as a radical that can be convertedoxidatively into carboxy, for example, hydroxymethyl, or formyloptionally formed in situ.

Starting from compounds of formula II wherein X₁ is hydroxymethyl orformyl, carboxy R₃ can be produced by means of oxidation. The oxidationis carried out, for example, in an inert solvent, such as in a loweralkanecarbexylic acid, e.g. acetic acid, a ketone, e.g. acetone, anether, e.g. tetrahydrofuran, a heterocyclic aromatic compound, e.g.pyridine, or in water, or in a mixture thereof, if necessary withcooling or heating, e.g. in a temperature range of from approximately 0°to approximately +150° C. There come into consideration as oxidizingagents, for example, oxidizing transition metal compounds, especiallythose with elements of sub-group I, VI or VII. There may be mentioned asexamples: silver compounds, such as silver nitrate, oxide andpicolinate, chromium compounds, such as chromium trioxide and potassiumdichromate, and manganese compounds, such as potassium,tetrabutylammonium and benzyltriethylammonium permanganate. Otheroxidizing agents are, for example, suitable compounds with elements ofmain group IV, such as lead dioxide, or halogen/oxygen compounds, suchas sodium iodate or potassium periodate. A radical X₁ that can beconverted into 5-tetrazolyl R₃ is, for example, cyano or N-protected5-tetrazolyl.

In order to prepare compounds of formula I wherein R₃ is 5-tetrazolyl,there is used as starting material, for example, a compound of formulaII wherein X₁ is cyano, which is reacted with an azide, for example withHN₃ or especially a salt, such as an alkali metal salt, thereof, or withan organotin azide, such as a tri-lower alkyltin or triaryltin azide.Preferred azides are, for example, sodium and potassium azide and alsotri-C₁ -C₄ alkyl-, e.g. triethyl- or tributyl-tin azide, andtriphenyltin azide.

There come into consideration as protecting groups of N-protected5-tetrazolyl R₃ the protecting groups customarily used in tetrazolechemistry, especially triphenylmethyl, unsubstituted or substituted,e.g. nitro-substituted, benzyl, such as 4-nitrobenzyl, loweralkoxymethyl, such as methoxy- or ethoxy-methyl, lower alkylthiomethyl,such as methylthiomethyl, and 2-cyanoethyl, also lower alkoxy-loweralkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl, and alsophenacyl. The removal of the protecting groups is carried out inaccordance with known methods, for example as described in J. Green,Protective Groups in Organic Synthesis, Wiley-Interscience (1980). Forexample triphenylmethyl is customarily removed by hydrolysis, especiallyin the presence of an acid, or by hydrogenolysis in the presence of ahydrogenation catalyst, 4-nitrobenzyl is removed, for example, byhydrogenolysis in the presence of a hydrogenation catalyst, methoxy- orethoxy-methyl is removed, for example, by treatment with a tri-loweralkyltin bromide, such as triethyl- or tributyl-tin bromide,methylthiomethyl is removed, for example, by treatment withtrifluoroacetic acid, 2-cyanoethyl is removed, for example, byhydrolysis, for example with sodium hydroxide solution,2-methoxyethoxymethyl is removed, for example, by hydrolysis, e.g. withhydrochloric acid, and benzyloxymethyl and phenacyl are removed, forexample, by hydrogenolysis in the presence of a hydrogenation catalyst.

A radical X₁ that can be converted into PO₂ H₂ or PO₃ H₂ R₃ is, forexample, a functional derivative of PO₂ H₂ or PO₃ H₂ respectively.

A corresponding radical X₁ that can be converted into R₃ is, forexample, a group --N₂ ⁺ A⁻, wherein A⁻ is an anion of an acid, such as amineral acid. Corresponding diazonium compounds are, for example,reacted in a manner known per se with a P(III) halide, such as PCl₃ orPBr₃, and worked up hydrolytically, compounds of formula I wherein R₃ isPO₃ H₂ being obtainable.

A radical X₁ that can be converted into SO₃ H R₃ is, for example, themercapto group. Starting compounds of formula II containing such a groupare oxidized, for example by oxidation processes known per se, tocompounds of formula I wherein R₃ is SO₃ H. There come intoconsideration as oxidizing agents, for example, inorganic peracids, suchas peracids of mineral acids, e.g. periodic acid or persulfuric acid,organic peracids, such as percarboxylic or persulfonic acids, e.g.performic, peracetic, trifluoroperacetic or perbenzoic acid orp-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids,e.g. mixtures of hydrogen peroxide and acetic acid. Frequently theoxidation is carried out in the presence of suitable catalysts. Theremay be mentioned as catalysts suitable acids, such as unsubstituted orsubstituted carboxylic acids, e.g. acetic acid or trifluoroacetic acid,and transition metal oxides, such as oxides of elements of sub-group VI,e.g. molybdenum oxide or tungsten oxide. The oxidation is carried outunder mild conditions, e.g. at temperatures of from approximately -50°to approximately +100° C.

The starting material of formula II is obtainable, for example, byreacting a compound of formula ##STR12## or a salt thereof, wherein X₃is one of the above-mentioned amino-protecting groups, for examplephthaloyl, with a compound of formula

    Ar--X--X.sub.4                                             (IIb)

wherein X₄ is reactive esterified hydroxy, in the presence of a base. Inthe next reaction step, the amino-protecting group is removed in amanner known per se, for example the phthaloyl group is removed bytreatment with hydrazine hydrate. A compound of formula ##STR13## soobtainable is then reacted with a compound of formula ##STR14## whereinX₄ is a nucleofugal leaving group, such as a diazonium radical orreactive esterified hydroxy, in the presence of base, to form a compoundof formula II wherein R₁ is hydrogen. If desired a correspondingcompound may be N-alkylated or N-acylated in a manner known per se toform a compound of formula II.

Reactive esterified hydroxy is especially hydroxy esterified by a stronginorganic acid or organic sulfonic acid, for example halogen, such aschlorine, bromine or iodine, or sulfonyloxy, such as hydroxysulfonyloxy,halosulfonyloxy, e.g. fluorosulfonyloxy, unsubstituted or substituted,e.g. halosubstituted, C₁ -C₇ alkanesulfonyloxy, e.g. methane- ortrifluoromethane-sulfonyloxy, C₅ -C₇ cycloalkanesulfonyloxy, e.g.cyclohexanesulfonyloxy, or unsubstituted or substituted, e.g. C₁ -C₇alkyl- or halo-substituted, benzenesulfonyloxy, e.g. p-bromophenyl- orp-toluene-sulfonyloxy, especially halogen, such as chloride, bromide oriodide, as well as sulfonyloxy, such as methane- orp-toluene-sulfonyloxy.

Reactive esterified hydroxy is preferably halogen, such as chloride,bromide or iodide, as well as sulfonyloxy, such as methane- orp-toluene-sulfonyloxy.

A specific method of preparing compounds of formula II is describedespecially in working Example 1.

The starting materials of formulae IIa, IIb and IId are known or can beprepared according to methods known per se.

Variant b)

There come into consideration as the amino-protecting group X₂ theprotecting groups customarily used in peptide chemistry, especiallytriphenylmethyl, unsubstituted or substituted, e.g. nitro-substituted,benzyl, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- orethoxymethyl, lower alkylthiomethyl, such as methylthiomethyl, and2-cyanoethyl, also lower alkoxy-lower alkoxymethyl, such as2-methoxyethoxymethyl, benzyloxymethyl and also phenacyl. The removal ofthe protecting groups is carried out in accordance with known methods,for example as described in J. Green, Protective Groups in OrganicSynthesis, Wiley-Interscience (1980). For example triphenylmethyl iscustomarily removed by hydrolysis, especially in the presence of anacid, or by hydrogenolysis in the presence of a hydrogenation catalyst,4-nitrobenzyl is removed, for example, by hydrogenolysis in the presenceof a hydrogenation catalyst, methoxy- or ethoxy-methyl is removed, forexample, by treatment with a tri-lower alkyltin bromide, such astriethyl- or tributyl-tin bromide, methylthiomethyl is removed, forexample, by treatment with trifluoroactic acid, 2-cyanoethyl is removed,for example, by hydrolysis, for example with sodium hydroxide solution,2-methoxyethoxymethyl is removed, for example, by hydrolysis, e.g. withhydrochloric acid, and benzyloxymethyl and phenacyl are removed, forexample, by hydrogenolysis in the presence of a hydrogenation catalyst.

The starting material of formula III is obtainable, for example, byreacting one of the compounds described hereinbefore of formula##STR15## with a compound of formula ##STR16## wherein X₄ is anucleofugal leaving group, such as a diazonium radical or reactiveesterified hydroxy, in the presence of a base to form a compound offormula II wherein R₁ is hydrogen, and then introducing theamino-protecting group in a manner known per se.

Variant c)

A nucleofugal leaving group X₅ is, for example, a diazonium radical oris reactive esterified hydroxy as defined hereinbefore. X₅ isadvantageously halogen, such as chlorine or bromine, or sulfonyloxy,such as methanesulfonyloxy or 4-nitrophenylsulfonyloxy.

The reaction is carried out in a manner known per se, advantageously inthe presence of one of the bases specified hereinbefore.

Some of the starting materials are known, or they can be preparedaccording to methods known per se.

The preparation of the starting material of formula IVa is carried out,for example, as described in connection with the preparation ofcompounds of formula III in Variant b).

Variant d)

There comes into consideration as the nucleofugal leaving groupespecially reactive esterified hydroxy, which, for example, is asdefined hereinbefore.

The reaction is carried out in a manner known per se, advantageously inthe presence of one of the bases specified hereinbefore.

The reaction is advantageously carried out with compounds of formula Vawherein R₃ is other than carboxy. The reaction is especiallyadvantageously carried out with compounds of formula Va wherein R₁ isother than hydrogen.

Some of the starting materials are known, or they can be preparedaccording to methods known per se.

To prepare a compound of formula (Va), for example a compound of formulaIIc is used as starting material and is reacted analogously to Variantc) with a compound of formula IVb or IVc, advantageously in the presenceof one of the bases defined hereinbefore.

Variant e)

The reaction is carried out in a manner known per se.

The reductive alkylation (X₇ =oxo) is carried out in the presence ofcustomary reducing agents, whereas the substitutive N-alkylation (X₇=reactive esterified hydroxy together with hydrogen) is carried outpreferably in the presence of one of the bases defined hereinbefore.

Some of the starting materials are known, or they can be preparedaccording to methods known per se.

A compound of formula I obtainable according to the process or in someother manner may be converted in a manner known per se into a differentcompound of formula I.

If one of the variables contains amino, corresponding compounds I may beN-(ar)alkylated in a manner known per se; similarly, carbamoyl orradicals containing carbamoyl may be N-(ar)alkylated. The (ar)alkylationis carried out, e.g., with an (aryl-)C₁ -C₇ alkyl halide, e.g. bromideor iodide, an (aryl-)C₁ -C₇ alkanesulfonate, e.g. methanesulfonate orp-toluenesulfonate, or a di-C₁ -C₇ alkyl sulfate, e.g. dimethyl sulfate,preferably under basic conditions, such as in the presence of sodiumhydroxide solution or potassium hydroxide solution, and advantageouslyin the presence of a phase transfer catalyst, such as tetrabutylammoniumbromide or benzyltrimethylammonium chloride, in which case, however,more strongly basic condensation agents, such as alkali metal amides,hydrides or alcoholates, e.g. sodium amide, sodium hydride or sodiumethanolate, may be necessary.

A compound of formula I wherein R₁ is hydrogen may be acylated in amanner known per se to a compound of formula I wherein R₁ is acyl. Thereaction is carried out, for example, with a compound of formula R₁ --OHor a reactive derivative thereof. Reactive derivatives of compounds offormula R₁ --OH are, for example, reactive anhydrides derived therefrom.

Anhydrides of acids of formula R₁ --OH may be symmetric or preferablymixed anhydrides of those acids, for example anhydrides with inorganicacids, such as acid halides, especially acid chlorides (obtainable, forexample, by treatment of the corresponding acid with thionyl chloride,phosphorus pentachloride or oxalyl chloride; acid chloride method),azides (obtainable, for example, from a corresponding acid ester via thecorresponding hydrazide by treatment thereof with nitrous acid; azidemethod), anhydrides with carbonic acid semiesters, for example carbonicacid lower alkyl semiesters (obtainable, for example, by treatment ofthe corresponding acid with chloroformic acid lower alkyl esters or witha 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, e.g.1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixed O-alkylcarbonicacid anhydrides method), anhydrides with dihalogenated, especiallydichlorinated, phosphoric acid (obtainable, for example, by treatment ofthe corresponding acid with phosphorus oxychloride; phosphorusoxychloride method), anhydrides with other phosphoric acid derivatives(for example those obtainable withphenyl-N-phenylphosphoramidochloridate) or with phosphorous acidderivatives, or anhydrides with organic acids, such as mixed anhydrideswith organic carboxylic acids (obtainable, for example, by treatment ofthe corresponding acid with an unsubstituted or substituted loweralkane- or phenyl-lower alkane-carboxylic acid halide, for examplephenylacetic acid chloride, pivalic acid chloride or trifluoroaceticacid chloride; mixed carboxylic acid anhydrides method) or with organicsulfonic acids (obtainable, for example, by treatment of a salt, such asan alkali metal salt, of the corresponding acid with a suitable organicsulfonic acid halide, such as a lower alkane- or aryl-, for examplemethane- or p-tolUene-sulfonic acid chloride; mixed sulfonic acidanhydrides method), as well as symmetric anhydrides (obtainable, forexample, by condensation of the corresponding acid in the presence of acarbodiimide or 1-diethylaminopropyne; symmetric anhydrides method).

Condensation to form an amide bond may be carried out in a manner knownper se, for example as described in standard works, such as Houben-Weyl,"Methoden der organischen Chemie", 4th edition, Volume 15/II, GeorgThieme Verlag, Stuttgart 1974, "The Peptides" (editors E. Gross and J.Meienhofer), Volumes 1 and 2, Academic Press, London and New York,1979/1980, or M. Bodanszky, "Principles of Peptide Synthesis",Springer-Verlag, Berlin 1984.

The condensation may be carried out in the presence of one of thecustomary condensation agents. Customary condensation agents are, forexample, carbodiimides, for example diethyl-, dipropyl-,N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide or especiallydicyclohexylcarbodiimide, also suitable carbonyl compounds, for examplecarbonyldiimidazole, 1,2-oxazolium compounds, for example2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate and2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylaminocompound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,and also activated phosphoric acid derivatives, for examplediphenylphosphoryl azide, diethylphosphoryl cyanide,phenyl-N-phenylphosphoramidochloridate,bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride or1-benzotriazolyloxy-tris(dimethylamino)-phosphonium hexafluorophosphate.

If desired an organic base is added, for example a tri-lower alkylaminehaving bulky radicals, such as ethyldiisopropylamine, or a heterocyclicbase, for example pyridine, 4-dimethylaminopyridine or preferablyN-methylmorpholine.

The condensation of acid anhydrides With amines may be effected, forexample, in the presence of inorganic carbonates, for example alkalimetal carbonates or hydrogen carbonates, such as sodium or potassiumcarbonate or hydrogen carbonate (usually together with a sulfate).

The condensation is carried out preferably in an inert, polar, aprotic,preferably anhydrous solvent or solvent mixture, for example in acarboxylic acid amide, for example formamide or dimethylformamide, ahalogenated hydrocarbon, for example methylene chloride, carbontetrachloride or chlorobenzene, a ketone, for example acetone, a cyclicether, for example tetrahydrofuran, an ester, for example ethyl acetate,or a nitrile, for example acetonitrile, or in a mixture thereof, asappropriate at reduced or elevated temperature, for example in atemperature range of from approximately -40° C. to approximately +100°C., preferably from approximately -10° C. to approximately +50° C., and,where appropriate, under an inert gas atmosphere, for example a nitrogenatmosphere.

Reactive acid derivatives may also be formed in situ.

In compounds of formula I that contain an esterified carboxy group assubstituent, such a group may be converted into a free carboxy group,for example by means of hydrolysis, for example in the presence of abasic agent or an acid agent, such as a mineral acid.Tert-butoxycarbonyl, for example, may furthermore be converted intocarboxy, for example in a manner known per se, such as by treatment withtrihaloacetic acid, such as trifluoroacetic acid, advantageously underanhydrous conditions, and benzyloxycarbonyl may be converted intocarboxy, for example, by catalytic hydrogenation in the presence of ahydrogenation catalyst, for example in the manner described below.

In addition, in compounds of formula I that have a carboxy group assubstituent (especially if R₃ is other than carboxy), the carboxy groupmay be converted, for example by treatment with an alcohol, such as alower alkanol, in the presence of a suitable esterifying agent, such asan acid reagent, e.g. an inorganic or organic acid or a Lewis acid, e.g.zinc chloride, or a water-binding condensation agent, e.g. acarbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by treatmentwith a diazo reagent, such as a diazo-lower alkane, e.g. diazomethane,into a correspondingly esterified carboxy group. The latter may also beobtained by treating compounds of formula I wherein the carboxy group isin free form or in the form of a salt, such as an ammonium or metalsalt, e.g. an alkali metal salt, such as a sodium or potassium salt,with a C₁ -C₇ alkyl halide, e.g. methyl or ethyl bromide or iodide, orwith an organic sulfonic acid ester, such as a corresponding C₁ -C₇alkyl ester, e.g. methanesulfonic acid or p-toluenesulfonic acid methylester or ethyl ester.

Compounds of formula I that contain an esterified carboxy group assubstituent may be converted into different ester compounds of formula Iby transesterification, e.g. by treatment with an alcohol, customarilywith an alcohol higher than that corresponding to the esterified carboxygroup in the starting material, in the presence of a suitabletransesterification agent, such as a basic agent, e.g. an alkali metalC₁ -C₇ alkanoate, C₁ -C₇ alkanolate or cyanide, such as sodium acetate,methanolate, ethanolate, tert-butanolate or cyanide, or of a suitableacid agent, where necessary with removal of the alcohol formed, e.g. bydistillation. It is also possible to use as starting material acorresponding so-called activated ester of formula I that contains anactivated esterified carboxy group as substituent (see below) andconvert that into a different ester by treatment with a C₁ -C₇ alkanol.

In compounds of formula I that contain a carboxy group as substituent,this may also first of all be converted into a reactive derivative, suchas an anhydride (also a mixed anhydride), an acid halide, e.g. an acidchloride (e.g. by treatment with a thionyl halide, e.g. thionylchloride), an anhydride with a formic acid ester, e.g. a formic acid C₁-C₇ -alkyl ester (e.g. by treatment of a salt, such as an ammonium oralkali metal salt, with a haloformic, such as a chloroformic, acidester, such as a C₁ -C₇ alkyl ester), or an activated ester, such as acyanomethyl, nitrophenyl, e.g. 4-nitrophenyl, or polyhalophenyl, e.g.pentachlorophenyl, ester (e.g. by treatment with a corresponding hydroxycompound in the presence of a suitable condensation agent, such asN,N'-dicyclohexylcarbodiimide), and such a reactive derivative may thenbe reacted with a corresponding alcohol component so as to obtaincorresponding ester compounds of formula I. Those may be obtaineddirectly or by way of intermediate compounds; for example an activatedester, such as a 4-nitrophenyl ester, of a compound of formula Icontaining a carboxy group may first of all be reacted with a1-unsubstituted imidazole and the resulting 1-imidazolylcarbonylcompound may be reacted with a corresponding ester component.

If an aromatic ring contains a hydrogen atom as substituent, then thatmay be replaced by a halogen atom in customary manner using ahalogenating agent, e.g. by bromine using bromine, hypobromic acid, anacylhypobromite or another organic bromine compound, e.g.N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridiniumperbromide, dioxane dibromide, 1,3-dibromo-5,5-dimethylhydantoin or2,4,4,6-tetrabromo-2,5-cyclohexanedien-1-one, or by chlorine usingelemental chlorine, e.g. in a halogenated hydrocarbon, such aschloroform, and with cooling, e.g. to approximately -10° C.

If an aromatic ring contains an amino group, then that may be diazotisedin customary manner, e.g. by treatment with a nitrite, e.g. sodiumnitrite, in the presence of a suitable protonic acid, e.g. a mineralacid, the reaction temperature advantageously being maintained belowapproximately 5° C. The diazonium group so obtainable, which is in saltform, may be substituted according to conventional processes, forexample as follows: by a hydroxy group analogously to decomposition tophenol in the presence of water; by an alkoxy group by treatment with acorresponding alcohol, for which energy must be supplied; by thefluorine atom analogously to the Schiemann reaction in the thermolysisof corresponding diazonium tetrafluoroborates; or by chlorine, bromine,iodine or the cyano group analogously to the Sandmeyer reaction byreaction with corresponding Cu(I) salts, initially with cooling, e.g. tobelow approximately 5° C., and then with heating, e.g. to fromapproximately 60° to approximately 150° C.

The invention relates especially to the processes described in theExamples.

Salts of compounds of formula I may be prepared in a manner known perse. For example acid addition salts of compounds of formula I areobtained by treatment with a suitable acid or a suitable ion exchangereagent. Salts of compounds I may be converted into free compounds I incustomary manner, and acid addition salts may be converted into freecompounds I e.g. by treatment with a suitable basic agent or a suitableion exchange reagent.

Salts of compounds I may be converted into different salts of compoundsI in a manner known per se.

Depending on the reaction procedure and reaction conditions, compounds Ihaving salt-forming, especially basic, properties, may be obtained infree form or in the form of salts.

Owing to the close relationship between the compounds I in free form andin the form of their salts, hereinbefore and hereinafter any referenceto the free compound I and its salts should be understood as includingalso the corresponding salts and the free compound I, respectively,where appropriate and expedient.

The compounds I, including the salts of salt-forming compounds, may alsobe obtained in the form of their hydrates and/or may include othersolvents, e.g. solvents used for crystallisation.

Depending on the choice of starting materials and procedures, thecompounds I and their salts may be in the form of one of the possibleisomers or a mixture thereof, for example depending on the number andthe absolute and relative configuration of the asymmetric carbon atomsthey may be in the form of pure isomers, such as antipodes and/ordiastereoisomers, or in the form of mixtures of isomers, such asmixtures of enantiomers, e.g. racemates, mixtures of diastereoisomers ormixtures of racemates.

Resulting mixtures of diastereoisomers and mixtures of racemates can beseparated in known manner into the pure diastereoisomers or racemates onthe basis of the physicochemical differences between the constituents,for example by fractional crystallisation. Resulting mixtures ofenantiomers, such as racemates, may be resolved into the opticalantipodes according to known methods, for example by recrystallisationfrom an optically active solvent, chromatography using chiraladsorbents, by means of suitable microorganisms, by cleavage withspecific immobilised enzymes, by the formation of inclusion compounds,e.g. using chiral crown ethers, only one enantiomer being complexed, orby conversion into diastereoisomeric salts, for example by reaction of abasic end-product racemate with an optically active acid, such as acarboxylic acid, for example tartaric acid or malic acid, or sulfonicacid, e.g. camphorsulfonic acid, and separation of the mixture ofdiastereoisomers obtained in that manner, for example on the basis oftheir different solubilities, into the diastereoisomers, from which thedesired enantiomer can be freed by the action of suitable agents.Advantageously, the more active enantiomer is isolated.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining steps are carried out, or inwhich a starting material is used in the form of a derivative or saltand/or its racemates or antipodes or, especially, is formed under thereaction conditions.

The starting materials and intermediates used in the process of thepresent invention are preferably those which lead to the compounds Idescribed at the beginning as being especially valuable. The inventionextends also to novel starting materials and intermediates for thepreparation of compounds I, to the use thereof and to a process for thepreparation thereof, the variables A, X, R₁, R₂, R₃ and R₄ having themeanings given for the compounds I.

The compounds of formula I and the pharmaceutically acceptable saltsthereof may be used, preferably in the form of pharmaceuticallyacceptable compositions, in a method for the prophylactic and/ortherapeutic treatment of the animal or human body, especially for thetreatment of disorders that are brought about by stimulation or blockingof the AT₂ -receptor.

The invention therefore also relates to pharmaceutical compositions thatcomprise as active ingredient a compound I in free form or in the formof a pharmaceutically acceptable salt as well as to a process for thepreparation thereof. The pharmaceutical compositions are for enteral,such as oral, or also rectal or parenteral administration towarm-blooded animals, and comprise the pharmacological active ingredienton its own or together with customary pharmaceutical excipients. Thepharmaceutical compositions contain e.g. approximately from 0.1% to100%, preferably from approximately 1% to approximately 60%, activeingredient. Pharmaceutical compositions for enteral and parenteraladministration are e.g. in unit dose forms, such as dragees, tablets,capsules or suppositories, and also ampoules. They are prepared in amanner known per se, e.g. by means of conventional mixing, granulating,confectioning, dissolving or lyophilising processes. For example,pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture, and processing the mixture or granules,if desired or necessary after the addition of appropriate excipients, toform tablets or dragee cores.

Suitable carriers are especially fillers, such as sugars, e.g. lactose,saccharose, mannitol or sorbitol, cellulose preparations and/or calciumphosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, andbinders, such as starch pastes, using e.g. corn, wheat, rice or potatostarch, gelatin, gum tragacanth, methylcellulose and/orpolyvinylpyrrolidone, and, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, cross-linkedpolyvinylpyrrolidone, agar or alginic acid or a salt thereof, such assodium alginate. Excipients are especially flow conditioners andlubricants, e.g. silicic acid, talc, stearic acid or salts thereof, suchas magnesium or calcium stearate, and/or polyethylene glycol. Drageecores are provided with suitable, optionally enteric, coatings, therebeing used, inter alia, concentrated sugar solutions which may comprisegum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/ortitanium dioxide, or coating solutions in suitable organic solvents orsolvent mixtures, or, for the preparation of enteric coatings, solutionsof suitable cellulose preparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Dyes or pigments may be added tothe tablets or dragee coatings, e.g. for identification purposes or toindicate different doses of active ingredient.

Other orally administrable pharmaceutical compositions are dry-filledcapsules consisting of gelatin, and also soft sealed capsules consistingof gelatin and a plasticiser, such as glycerol or sorbitol. Thedry-filled capsules may contain the active ingredient in the form ofgranules, for example in admixture with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and, if desired, stabilisers. In soft capsules, the activeingredient is preferably dissolved or suspended in suitable liquids,such as fatty oils, paraffin oil or liquid polyethylene glycols, towhich stabilisers may also be added.

There come into consideration as rectally administrable pharmaceuticalcompositions e.g. suppositories that consist of a combination of theactive ingredient with a suppository base. Suitable suppository basesare e.g. natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols and higher alkanols. It is also possible to usegelatin rectal capsules, which contain a combination of the activeingredient with a base material. There come into consideration as basematerials e.g. liquid triglycerides, polyethylene glycols and paraffinhydrocarbons.

There are suitable for parenteral administration especially aqueoussolutions of an active ingredient in water-soluble form, e.g. in theform of a water-soluble salt, or also suspensions of the activeingredient, such as corresponding oily injection suspensions, therebeing used suitable lipophilic solvents or vehicles, such as fatty oils,e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate ortriglycerides, or aqueous injection suspensions that compriseviscosity-increasing substances, e.g. sodium carboxymethylcellulose,sorbitol and/or dextran, and, if desired, also stabilisers.

The dosage of the active ingredient may depend on various factors, suchas mode of administration, species of warm-blooded animal, age and/orindividual condition. For a patient weighing approximately 75 kg, theestimated approximate daily dose in the case of oral administration isnormally from approximately 10 mg to approximately 2250 mg, especiallyfrom approximately 10 mg to approximately 250 mg.

The following Examples illustrate the invention described above; theyare not, however, intended to limit the scope thereof in any way.Temperatures are quoted in degrees Celsius (°C.).

EXAMPLE 1 3-(1-(S)-Carboxy-3-cyclohexyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one

5.3 g of 3-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneof the diastereoisomeric mixture (the reaction may, however, also becarried out starting from the pure diastereoisomers as a result ofwhich, with careful hydrolysis, no noticeable racemisation occurs) aredissolved in 200 ml of methanol, 50 ml of water and 16 ml of 2N aqueousNaOH solution are added and then the batch is stirred at roomtemperature for 23 h. 16 ml of 2N hydrochloric acid (pH approx. 5) areadded, the mixture is concentrated in a rotary evaporator, the residueis taken up in ethyl acetate and washed twice with water and once withbrine, and the organic phases are dried over magnesium sulfate andconcentrated. The crude product is obtained. The purification orseparation is carried out by means of flash chromatography (240 g ofsilica gel, eluant methylene chloride/methanol 98:2, later 9:1). Theappropriate fractions are concentrated by evaporation and thenrecrystallised from ethyl acetate.

less polar diastereoisomer: m.p. 151-153; R_(f) value: 0.81

more polar diastereoisomer: m.p. 157-158; R_(f) value: 0.58.

A 1:1 mixture of a) methylene chloride and b) methylenechloride/methanol/water/acetic acid (150:50:10:1) is used as eluant inthe determination of the R_(f) value. ##STR17##

The starting material may be obtained, for example, as follows:

a)3-(R/S)-N-Phthaloylamino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one

5 g of 3-(R/S)-N-phthaloyl-1-2,3,4,5-tetrahydro-benzazepin-2-one (Helv.Chim. Acta 71 (2), 337, 1988) are dissolved in 40 ml of DMF and, whilecooling with an ice bath, 1.2 g of sodium hydride (55% in oil) areadded. The mixture is then heated to 60° C. and cooled again to roomtemperature. Over a period of 5 minutes 4.13 g of p-isopropylbenzylchloride (Fairfield I-200700) are then added dropwise while cooling withan ice bath. The batch is stirred for 15 minutes at room temperature andthen overnight at 60° C. After cooling, 30 ml of water are added to thereaction mixture. The mixture is then extracted 4 times with ethylacetate, and the organic phases are washed twice with water and oncewith brine, dried over sodium sulfate and concentrated. The residue isseparated by means of flash chromatography (200 g of silica gel, eluantethyl acetate/hexane 1:2). R_(f) value (ethyl acetate/hexane 1:2): 0.7.

b)3-(R/S)-Amino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one

2.8 ml of hydrazine hydrate are added to 5.6 g of3-(R/S)-N-phthaloylamino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-onein 120 ml of ethanol. The mixture is heated at reflux for 2.5 h, cooledin an ice bath and filtered with suction (washing with ethanol). Flashchromatography (80 g of silica gel, eluant methylene chloride/methanol95:5) yields the pure product. R_(f) value (methylene chloride/methanol9:1): 0.71.

c) 3-(1-(S)-Ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one

1.5 g of3-(R/S)-amino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand 2.23 g of (R)-alpha-(4-nitrophenyl)-sulfonyl!oxy!-4-cyclohexylbutyric acid ethyl ester(Helv. Chim. Acta 71 (2), 337, 1988) are combined and, at 40° C., 0.67ml of N-methylmorpholine is added. The mixture is heated at 75° C. for15 h, cooled, diluted with ethyl acetate, washed with aqueous sodiumhydrogen carbonate solution and water and finally with dilutehydrochloric acid and brine. Flash chromatography (80 g of silica gel,eluant ethyl acetate/hexane 1:2) yields the two diastereoisomers which,after being dissolved in ethyl acetate/tetrahydrofuran, were eachconverted separately into the corresponding hydrochloride with 3equivalents of 1N hydrochloric acid. R_(f) values of the free bases(eluant: ethyl acetate/hexane 1:2):

less polar component: 0.70;

more polar component: 0.46.

hydrochloride of the less polar component: m.p. 64°-66° C.;

hydrochloride of the more polar component: m.p. 66°-68° C.

The two diastereoisomers may be hydrolysed either separately, or in theform of a mixture (chromatographic separation at the acid stage) to formthe corresponding acids.

EXAMPLE 2 3-(1-(S)-Carboxy-3-phenyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one

The target compound may be prepared in a manner analogous, for exampleas described in Example 1. Starting from 3-(1-(R/S)-ethoxycarbonyl-3-phenyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one(the two diastereoisomers are hydrolysed separately), the two purediastereoisomeric acids are obtained by hydrolysis with dilute sodiumhydroxide solution, working up and flash chromatography (eluant:methylene chloride/methanol: 9:1):

m.p. a) 150°-151° C. (starting from the more polar ethyl ester)

m.p. b) 147°-148° C. (starting from the less polar ethyl ester).

The two diastereoisomers may also be hydrolysed in the form of a mixtureto form the corresponding acids, by means chromatographic separation atthe acid stage.

The starting material may be obtained, for example, as follows:

a) 3-(1-(S)-Ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one

Was prepared analogously to Example 1c) starting from3-(R/S)-amino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand (R)-alpha- (4-nitrophenyl)sulfonyl!-oxy!-4-phenylbutyric acid ethylester (Helv. Chim. Acta 71 (2), 337, 1988). Flash chromatography(eluant: ethyl acetate/hexane: 1:4) yields the two purediastereoisomeric forms which, after being dissolved in ethylacetate/tetrahydrofuran, are each converted separately into thecorresponding hydrochloride by treatment with 3 equivalents of 1Nhydrochloric acid. R_(f) values of the free bases (eluant ethylacetate/hexane):

less polar component: 0.49

more polar component: 0.36.

m.p.: 68°-70° C. (hydrochloride of the less polar component),

m.p.: 71°-72° C. (hydrochloride of the more polar component).

EXAMPLE 3

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;diastereoisomer A: m.p. 160°-162°; diastereoisomer B: m.p. 158°-159°;

3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;diastereoisomer A: m.p. 158° C.; diastereoisomer B: m.p. 182°-183°;

3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;diastereoisomer A: m.p. 168°-170° C.; diastereoisomer B: m.p. 216°-220°;

3-N-acetyl-N-(1-(S)-carboxy-3-phenyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(1-(S)-carboxy-3-phenyl-propyl)-amino!-1-benzyl-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-benzyl-2,3,4,5-tetrahydro-benzazepin-2-one;diastereoisomer A: m.p. 98°-101° C.; diastereoisomer B: m.p. 206°-208°;

3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;diastereoisomer A: m.p. 185°-186° C.; diastereoisomer B: m.p. 95°-100°;

3-(1-(S)-carboxy-2-phenyl-ethyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one-hydrochloride;diastereoisomer A: m.p. 158°; diastereoisomer B: m.p. 190°.

EXAMPLE 4

In an analogous manner, for example, as described in Example 1 or 2, thefollowing may be prepared:

3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one(less polar diastereoisomer), analogously to Example 1 by treating 182mg of 3-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one(less polar diastereoisomer) with aqueous sodium hydroxide solution,R_(f) value (eluant methylene chloride/methanol 9:1) 0.43.

The starting material may be prepared, for example, as follows:

Starting from 50 g of3-N-phthaloylamino-2,3,4,5-tetrahydro-benzazepin-2-one, 17.9 g of sodiumhydride dispersion (55%) and 88.7 g of p-nitrobenzyl chloride in DMF,3-N-phthaloylamino-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneis obtained. R_(f) value (eluant ethyl acetate/hexane 1:1) 0.86.

The treatment of 33.5 g of3-N-phthaloylamino-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-onewith hydrazine hydrate in ethanol under reflux yields3-amino-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one. R_(f)value (eluant methylene chloride/methanol 9:1) 0.49.

The reaction of 15 g of3-amino-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with 22.1g of (R)-alpha- (4-nitrophenyl)sulfonyl!oxy!-4-cyclohexylbutyric acidethyl ester and 6.45 ml N-methylmorpholine yields the twodiastereoisomeric esters 3-(S)-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand 3-(R)-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.R_(f) values (eluant ethyl acetate/hexane 1:2) non-polar component 0.78,polar component 0.69.

EXAMPLE 5

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared: Starting from 199 mg of the polar component3-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one,in an analogous manner the more polar diastereoisomer of 3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneis obtained; R_(f) value (eluant methylene chloride/methanol 9:1) 0.33.

EXAMPLE 6

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand

3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.

The two products are obtained by hydrogenation at normal pressure withpalladium-on-carbon (10%) in methanol starting from the correspondingnitro derivatives, which are described in Example 4, FAB-MS: (M+H)⁺ 450.

EXAMPLE 7

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand

3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.

The two products are obtained analogously to Example 1 by hydrolysis ofthe corresponding ethyl esters with aqueous NaOH solution.

M.p. 161°-162° C. (less polar diastereoisomer), 158°-159° C. (more polardiastereoisomer).

The starting esters may be obtained analogously to Example 1 as follows:

Starting from 6.1 g of3-N-phthaloylamino-2,3,4,5-tetrahydro-benzazepin-2-one, 0.9 g of sodiumhydride dispersion (55%) and 5.48 g of p-tert-butylbenzyl chloride inDMF,3-N-phthaloylamino-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneis obtained. R_(f) value (eluant ethyl acetate/hexane 1:1) 0.87.

The treatment of 6.8 g of3-N-phthaloylamino-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-onewith hydrazine hydrate in ethanol under reflux yields3-amino-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one,R_(f) value (eluant methylene chloride/methanol 4:1) 0.61.

The reaction of 3.55 g of3-amino-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with2.5 g of (R)-alpha- (4-nitrophenyl)sulfonyl!oxy!-4-cyclohexylbutyricacid ethyl ester and 1.03 ml of N-methylmorpholine yields the twodiastereoisomeric esters 3-(S)-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand 3-(R)-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one,R_(f) values (eluant ethyl acetate/hexane 1:2) non-polar component 0.42,polar component 0.26.

EXAMPLE 8

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand

3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.

The two products are obtained analogously to Example 1 by hydrolysis ofthe corresponding ethyl esters with aqueous NaOH solution. M.p. 158° C.(less polar diastereoisomer), 182°-183° C. (more polar diastereoisomer).

The starting esters may be obtained analogously to Example 1 as follows:

Starting from 10 g of3-N-phthaloylamino-2,3,4,5-tetrahydro-benzazepin-2-one, 1.46 g of sodiumhydride dispersion (55%) and 6.9 g of p-methylbenzyl chloride in DMF,3-N-phthaloylamino-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneis obtained, R_(f) value (eluant ethyl acetate/hexane 1:1) 0.39.

The treatment of 9.9 g of3-N-phthaloylamino-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-onewith 5.5 ml of hydrazine hydrate in ethanol under reflux yields3-amino-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one, R_(f)value (eluant methylene chloride/methanol 9:1) 0.46.

The reaction of 5.4 g of3-amino-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with 8.84g of (R)-alpha- (4-nitrophenyl)sulfonyl!oxy!-4-cyclohexylbutyric acidethyl ester and 2.6 ml of N-methylmorpholine yields the twodiastereoisomeric esters 3-(S)-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand 3-(R)-(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one,R_(f) values (eluant ethyl acetate/hexane 1:2) non-polar component 0.58,polar component 0.39.

EXAMPLE 9

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(S)-(1-(S)-carboxy-2-phenylethyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-onehydrochloride and

3-(R)-(1-(S)-carboxy-2-phenylethyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-onehydrochloride.

The products are obtained by hydrogenation of the corresponding benzylesters at normal pressure in the presence of palladium-on-carbon (10%)in dioxane as solvent. M.p. 190° C. (non-polar diastereoisomer), 158° C.(polar diastereoisomer).

The starting materials may be prepared, for example, as follows:

Starting from 11 g of D-phenyllactic acid benzyl ester, 10.5 g of4-nitrobenzenesulfonyl chloride and 6 ml of triethylamine, (R)-alpha-(4-nitrophenyl)sulfonyl!oxy!-3-phenylpropionic acid benzyl ester isobtained. R_(f) value (eluant ethyl acetate/hexane 1:4) 0.3.

Starting from 2.55 g of (R)-alpha-(4-nitrophenyl)sulfonyl!oxy!-3-phenylpropionic acid benzyl ester, 800 mgof 3-amino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and0.88 ml of N-methylmorpholine, 3-(S)-(1-(S)-benzyloxycarbonyl-2-phenylethyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand 3-(R)-(1-(S)-benzyloxycarbonyl-2-phenylethyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneare obtained after flash chromatography (1 kg of silica gel, eluantpetroleum ether/ethyl acetate 3:1). R_(f) values (eluant ethylacetate/hexane 1:2) 0.34 (non-polar diastereoisomer), 0.18 (polardiastereoisomer).

EXAMPLE 10

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(S)-(1-(S)-carboxy-3-phenylpropyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-onehydrochloride and

3-(R)-(1-(S)-carboxy-3-phenylpropyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.

The products are obtained analogously to Example 1 by basic hydrolysisof the two corresponding ethyl esters in a mixture of methanol/water(10:1).

M.p. 209° C. for the polar diastereoisomer, 107° C. for the non-polardiastereoisomer.

The two starting esters may be prepared analogously to Example 2, forexample as follows:

Starting from 4.2 g of (R)-alpha-(4-nitrophenyl)sulfonyl!-oxy!3-phenylbutyric acid ethyl ester, 2 g of3-amino-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and 2.81ml of N-methylmorpholine, 3-(S)-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand 3-(R)-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydrobenzazepin-2-one are obtained after flash chromatography (1 kg of silicagel, eluant petroleum ether/ethyl acetate 3:1).

R_(f) values (eluant ethyl acetate/hexane 1:2) 0.37 (non-polardiastereoisomer), 0.23 (polar diastereoisomer).

The hydrochlorides are obtained by treatment with 3N HCl in ethylacetate.

EXAMPLE 11

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexylpropyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.

200 mg of 3-(S)-(1-(S)-N-benzyloxy-carbamoyl-3-cyclohexylpropyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneare hydrogenated in 10 ml of methanol under normal pressure in thepresence of 50 mg of palladium-on-carbon (10%) until saturation isreached. After removal of the catalyst by filtration and concentrationby evaporation the product is obtained in the form of an amorphouspowder. M.p. 110° C. (decomp.) R_(f) value (eluant chloroform/methanol9:1) 0.59.

The starting material may be prepared, for example, as follows:

400 mg of 3-(S)-(1-(S)-carboxy-3-cyclohexylpropyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.268 mg of O-benzylhydroxylamine hydrochloride, 328 mg ofO-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and718 mg of N-ethyl-diisopropylamine are stirred at room temperature for 3hours in 4.4 ml of DMF. The reaction mixture is taken up in ethylacetate, washed with 0.1N NaOH, water and 1N HCl, dried and concentratedby evaporation. Separation by means of flash chromatography (90 g ofsilica gel, eluant pentane/ethyl acetate 2:1) yields the product in theform of a resin. R_(f) value (eluant hexane/ethyl acetate 1:1) 0.52.

EXAMPLE 12

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared: 3-(S)-(1-(S)-carbamoyl-3-cyclohexylpropyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one400 mg of the product of Example 1 are stirred overnight at roomtemperature with 328 mg ofO-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 2ml of conc. aqueous ammonia in 6 ml of DMF. The reaction mixture istaken up in ethyl acetate and washed with water and the organic phase isdried and concentrated. The product is obtained by lyophilisation fromdioxane. R_(f) value (eluant hexane/ethyl acetate 1:1) 0.21.

EXAMPLE 13

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand

3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.

The two products are obtained by reductive amination of the twocompositions described in Example 6, 3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand 3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one,with hydrogen in the presence of formaldehyde with palladium-on-carbon(10%). M.p. 168°-170° C. (less polar diastereoisomer), 216°-220° C.(more polar diastereoisomer).

EXAMPLE 14

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared:

3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(benzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand

3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(benzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.

The two products are obtained analogously to Example 1 by hydrolysis ofthe corresponding ethyl esters with aqueous NaOH solution. M.p. 98°-101°C. (less polar diastereoisomer), 206°-208° C. (more polardiastereoisomer).

EXAMPLE 15

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared: 3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-oneand 3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.The two products are obtained analogously to Example 1 by hydrolysis ofthe corresponding ethyl esters with aqueous NaOH solution. M.p. 95°-100°C. (less polar diastereoisomer), 185°-186° C. (more polardiastereoisomer).

EXAMPLE 16

In an analogous manner, for example as described in Example 1 or 2, thefollowing may be prepared: 3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-N-acetylamino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.The product is obtained by treatment of the product described in Example1 with acetic anhydride and 4-dimethylaminopyridine in methylenechloride. FAB-MS: (M+H)⁺ 519.

EXAMPLE 17

In an analogous manner, for example as described in one of the aboveExamples, the following may be prepared:

3-(S)-(1-(S)-carbamoyl-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-phenyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-phenyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3--(S)-(1-(S)-carbamoyl-3-cyclohexyl-ethyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexyl-ethyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-phenyl-ethyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-phenyl-ethyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-cyclohexyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-phenyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-phenyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-cyclohexyl-ethyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexyl-ethyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-phenyl-ethyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-phenyl-ethyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-cyclohexyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-phenyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-phenyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-cyclohexyl-ethyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexyl-ethyl)-amino!1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-phenyl-ethyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-phenyl-ethyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-phenyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-phenyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-cyclohexyl-ethyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexyl-ethyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-carbamoyl-3-phenyl-ethyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;

3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-phenyl-ethyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one.

EXAMPLE 18

Tablets, each comprising 50 mg of active ingredient, e.g. 3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one,may be prepared as follows:

    ______________________________________                                        Composition (for 10 000 tablets):                                             ______________________________________                                        active ingredient       500.0  g                                              lactose                 500.0  g                                              potato starch           352.0  g                                              gelatin                 8.0    g                                              talc                    60.0   g                                              magnesium stearate      10.0   g                                              silicon dioxide (highly dispersed)                                                                    20.0   g                                              ethanol                 q.s.                                                  ______________________________________                                    

The active ingredient is mixed with the lactose and 292 g of potatostarch and the mixture is moistened with an alcoholic solution of thegelatin and granulated through a sieve. After drying the granules, theremainder of the potato starch, the talc, the magnesium stearate and thehighly dispersed silicon dioxide are added thereto and the mixture iscompressed to form tablets, each weighing 145.0 mg and comprising 50.0mg of active ingredient, which may, if desired, be provided withbreaking notches for the purpose of finer adjustment of the dose.

EXAMPLE 19

Film-coated tablets, each comprising 100 mg of active ingredient, e.g.3-(1-(S)-carboxy-3-phenyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one,may be prepared as follows:

    ______________________________________                                        Composition (for 1000 tablets):                                               ______________________________________                                        active ingredient      100.00  g                                              lactose                100.00  g                                              corn starch            70.00   g                                              talc                   8.50    g                                              calcium stearate       1.50    g                                              hydroxypropylmethylcellulose                                                                         2.36    g                                              shellac                0.64    g                                              water                  q.s.                                                   dichloromethane        q.s.                                                   ______________________________________                                    

The active ingredient, the lactose and 40 g of the corn starch are mixedand moistened with a paste prepared from 15 g of corn starch and water(with heating) and granulated. The granules are dried, and the remainderof the corn starch, the talc and the calcium stearate are added andmixed with the granules. The mixture is compressed to form tablets(weight: 280 mg) which are then film-coated with a solution of thehydroxypropylmethylcellulose and the shellac in dichloromethane (finalweight of the film-coated tablet: 283 mg).

EXAMPLE 20

In an analogous manner, for example as described in Examples 18 and 19,it is also possible to prepare tablets and film-coated tabletscomprising a different compound of formula I or a pharmaceuticallyacceptable salt of a compound of formula I, e.g. according to any one ofExamples 1 to 17.

We claim:
 1. A compound of the formula ##STR18## wherein Ar is aryl;X isC₁ -C₂ alkylene or a direct bond; R₁ is selected from the groupconsisting of hydrogen; lower alkyl; aryl-lower alkyl; and an acylselected from the group consisting of lower alkanoyl, aryl-loweralkanoyl and aroyl, each of which is either unsubstituted orindependently substituted by 1-3 substituents independently selectedfrom the group consisting of lower alkyl, aryl-lower alkyl, loweralkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-loweralkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl, nitro,halogen, trifluoromethyl, and amino, where said amino may beunsubstituted, mono- or independently di-substituted by lower alkyl,aryl-lower alkyl or aryl, or disubstituted by lower alkylene or loweralkyleneoxy-lower alkylene; R₂ is lower alkyl, hydroxy-lower alkyl,lower alkoxy-lower alkyl, aryl-lower alkoxy-lower alkyl, aryl-loweralkyl or C₃ -C₇ cycloalkyl-lower alkyl; R₃ is carboxy; 5-tetrazolyl, PO₂H₂, PO₃ H₂ or SO₃ H₂ ; alkoxycarbonyl; lower alkoxy-loweralkoxycarbonyl; aryl-lower alkoxycarbonyl; aryloxycarbonyl; carbamoyl;carbamoyl that (i) is monosubstituted by hydroxy, lower alkanesulfonyl,halo-lower alkanesulfonyl or by arylsulfonyl, (ii) is monosubstituted ordisubstituted, the substituents independently selected from the groupconsisting of lower alkyl, lower alkenyl, lower alkynyl and phenyl-loweralkyl, or (iii) is disubstituted by lower alkylene or by loweralkylene-X₁ -lower alkylene, wherein X₁ is selected from the groupconsisting of O, S and NH; the ring A is unsubstituted or mono- orpoly-substituted by substituents selected from the group consisting of:lower alkyl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy,lower alkoxy-lower alkoxy, aryl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, and amino,where said amino may be unsubstituted, mono- or independentlydi-substituted by lower alkyl, aryl-lower alkyl or by aryl, ordisubstituted by lower alkylene or lower alkyleneoxy-lower alkylene;"aryl" in each case above is an independently-selected "carbocyclic orheterocyclic aryl" which may be independently substituted by 1-3substituents independently selected from the group consisting of loweralkyl, "carbocyclic or heterocyclic aryl"-lower alkyl, loweralkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,"carbocyclic or heterocyclic aryl"-lower alkoxy, C₃ -C₇ cycloalkyl, C₃-C₇ cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, and amino,where said amino may be unsubstituted, mono- or independentlydi-substituted by lower alkyl, "carbocyclic or heterocyclic aryl"-loweralkyl or "carbocyclic or heterocyclic aryl", or disubstituted by loweralkylene or lower alkyleneoxy-lower alkylene: and "carbocyclic orheterocyclic aryl" is selected from the group consisting of phenyl,naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl, andthiazolyl;a stereoisomer or a metal, mineral, ammonium, or organic saltthereof.
 2. A compound according to claim 1 of formula I whereinAr isphenyl; X is C₁ -C₂ alkylene or a direct bond; R₁ is hydrogen, loweralkyl, lower alkyl that is substituted by phenyl, naphthyl, pyrrolyl,pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or by thiazolyl, loweralkanoyl, lower alkanoyl that is substituted by phenyl, naphthyl,pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or bythiazolyl, or benzoyl; R₂ is (i) lower alkyl, lower alkyl that issubstituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl,imidazolyl, isoxazolyl or by thiazolyl, or C₃ -C₇ cycloalkyl-loweralkyl, or (ii) hydroxy-lower alkyl, lower alkoxy-lower alkyl, or loweralkoxy-lower alkyl in which the lower alkoxy moiety is substituted byphenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl,isoxazolyl or by thiazolyl; R₃ is (i) carboxy, 5-tetrazolyl, PO₂ H₂, PO₃H₂ or SO₃ H₂ or (ii) lower alkoxycarbonyl, lower alkoxy-loweralkoxycarbonyl, phenyl-lower alkoxycarbonyl, benzoylcarbonyl, carbamoyl,lower alkylcarbamoyl, di-lower alkylcarbamoyl, phenyl-loweralkylcarbamoyl, diphenyl-lower alkylcarbamoyl, hydroxy-carbamoyl, loweralkanesulfonyl-carbamoyl, halo-lower alkanesulfonyl or phenylsulfonyl;the ring A and carbocyclic and heterocyclic aromatic radicals are,independently of one another, unsubstituted or mono- or poly-substitutedby substituents selected from the group consisting of: lower alkyl,lower alkyl that is substituted by phenyl, naphthyl, pyrrolyl, pyridyl,furyl, thienyl, imidazolyl, isoxazolyl or by thiazolyl, loweralkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl,nitro, halogen, trifluoromethyl, amino and amino that is monosubstitutedor disubstituted, the substituents being independent of one another, bylower alkyl, phenyl-lower alkyl or by phenyl, or disubstituted by loweralkylene or by lower alkyleneoxy-lower alkylene;a stereoisomer or ametal, mineral, ammonium, or organic salt thereof.
 3. A compoundaccording to claim 1 of formula I whereinAr is phenyl; X is C₁ -C₂alkylene or a direct bond; R₁ is hydrogen, lower alkyl, phenyl-loweralkyl, lower alkanoyl, phenyl-lower alkanoyl or benzoyl; R₂ is loweralkyl, phenyl-lower alkyl or C₃ -C₇ cycloalkyl-lower alkyl; R₃ iscarboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ or (ii) carbamoyl orhydroxy-carbamoyl; the ring A and carbocyclic and heterocyclic aromaticradicals are, independently of one another, unsubstituted or mono- orpoly-substituted by substituents selected from the group consisting of:lower alkyl, phenyl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy,lower alkoxy-lower alkoxy, phenyl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃-C₇ cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino andamino that is monosubstituted or disubstituted, the substituents beingindependent of one another, by lower alkyl, phenyl-lower alkyl or byphenyl, or disubstituted by lower alkylene or by lower alkyleneoxy-loweralkylene;a stereoisomer or a metal, mineral ammonium , or organic saltthereof.
 4. A compound according to claim 1 of formula I whereinAr isphenyl or phenyl substituted by C₁ -C₄ alkyl; X is C₁ -C₂ alkylene or adirect bond; R₁ is hydrogen, C₁ -C₄ alkyl or C₂ -C₅ alkanoyl; R₂ isphenyl-C₁ -C₄ alkyl or C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl; R₃ is carboxy,5-tetrazolyl, PO.sub. H₂, PO₃ H₂ or SO₃ H₂ ; the ring A is unsubstitutedor mono- or poly-substituted by substituents selected from the groupconsisting of: C₁ -C₄, alkyl halogen, C₁ -C₄ alkoxy-C₁ -C₄ alkyl, C₁ -C₄alkoxy, C₁ -C₄ alkoxy-C₁ -C₄ alkoxy, nitro, halogen andtrifluoromethyl;a stereoisomer or a metal, mineral, ammonium or organicsalt thereof.
 5. A compound according to claim 1 of formula I whereinAris phenyl substituted by C₁ -C₄ alkyl, lower alkoxy, halogen,trifluoromethyl, amino, lower alkylamino, di-lower alkylamino or bynitro; X is methylene; R₁ is hydrogen or C₂ -C₅ alkanoyl; R₂ isphenyl-C₁ -C₄ alkyl wherein phenyl is unsubstituted or is substituted byhalogen, trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄ alkoxy; or R₂ is C₃-C₇ cycloalkyl-C₁ -C₄ alkyl; R₃ is carboxy, carbamoyl orhydroxycarbamoyl; the ring A is unsubstituted or mono- orpoly-substituted by substituents selected from the group consisting of:C₁ -C₄ -alkyl, halogen, C₁ -C₄ alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁-C₄ alkoxy-C₁ -C₁ alkoxy, nitro, halogen and trifluoromethyl;astereoisomer or a metal, mineral, ammonium, or organic salt thereof. 6.A compound according to claim 1 of formula I whereinAr is phenyl orphenyl substituted, especially in the para-position, by C₁ -C₄ alkyl,such as p-isopropylphenyl; X is methylene; R₁ is hydrogen or C₂ -C₅alkanoyl; R₂ is phenyl-C₁ -C₄ alkyl or C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl;R₃ is carboxy or 5-tetrazolyl; the ring A is unsubstituted or is mono-or poly-substituted by substituents selected from the group consistingof: C₁ -C₄ -alkyl, halogen, C₁ -C₄ alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy,C₁ -C₄ -alkoxy-C₁ -C₄ alkoxy, nitro, halogen and trifluoromethyl;astereoisomer or a metal, mineral, ammonium, or organic salt thereof. 7.A compound according to claim 1 of formula (Ia) ##STR19## wherein R₁ ishydrogen;R₂ is phenyl-C₁ -C₄ alkyl, such as 2-phenyl-ethyl, or C₃ -C₇cycloalkyl-C₁ -C₄ alkyl, such as 2-cyclohexyl-ethyl; R₃ is carboxy; andR₄ is C₁ -C₄ alkyl, especially isopropyl, that is bonded especially inthe para-position;a stereoisomer or a metal, mineral, ammonium, ororganic salt thereof.
 8. A compound according to claim 1 of formula (Ib)##STR20## wherein R₁ is hydrogen;R₂ is phenyl-C₁ -C₄ alkyl, such as2-phenyl-ethyl, or C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl, such as2-cyclohexyl-ethyl; R₃ is carboxy; and R₄ is C₁ -C₄ alkyl, especiallyisopropyl;a stereoisomer or a metal, mineral, ammonium, or organic saltthereof.
 9. A compound according to claim 1 of formulae I wherein boththe carbon atom having the variables R₂ and R₃, and the heterocyclecarbon atom to which the amino group is bonded, have the(S)-configuration.
 10. A compound selected from3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-isopropyl-benzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-phenyl-propyl)-amino!-1-(p-isopropyl-benzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-N-acetyl-N-(1-(S)-carboxy-3-phenyl-propyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-phenyl-propyl)-amino!-1-benzyl-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-benzyl-2,3,4,5-tetrahydro-benzazepin-2-one;3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;and 3-(1-(S)-carboxy-2-phenyl-ethyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;ora salt thereof.
 11. A compound selected from3-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-aminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carboxy-2-phenylethyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(R)-(1-(S)-carboxy-2-phenylethyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carboxy-3-phenylpropyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(R)-(1-(S)-carboxy-3-phenylpropyl)-amino!-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-N-hydroxy-carbamoyl-3-cyclohexylpropyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carbamoyl-3-cyclohexylpropyl)-amino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-dimethylaminobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(benzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(benzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;3-(R)-(1-(S)-carboxy-3-cyclohexyl-propyl)-amino!-1-(p-methoxybenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;and 3-(S)-(1-(S)-carboxy-3-cyclohexyl-propyl)-N-acetylamino!-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one;ora salt thereof in each case.
 12. A process for the preparation of acompound of formula I, a stereoisomer or a salt thereof, whichcomprisesa) in a compound of formula ##STR21## wherein X₁ is a radicalthat can be converted into the variable R₃, or in a salt thereof,converting X₁ into the variable R₃ ; or, b) for the preparation of acompound of formula (I) wherein R₁, is hydrogen, or for the preparationof a salt thereof, in a compound of formula ##STR22## wherein X₂ is anamino-protecting group, or in a salt thereof, removing theamino-protecting group; or c) reacting a compound of formula ##STR23##with a compound of formula ##STR24## wherein X₅ is a nucleofugal leavinggroup, or with a compound of formula R₂ --CO--R₃ (IVc) or a saltthereof; or d) reacting a compound of formula ##STR25## with a compoundof formula X₆ --X--Ar (Vb), wherein X₆ is a nucleofugal leaving group,or with a salt thereof; or e) reacting a compound of formula ##STR26##wherein X₇ is (i) oxo or (ii) reactive esterified hydroxy together withhydrogen, with a compound of formula ##STR27## or with a salt thereof;and in each case, if desired, converting a compound of formula Iobtainable according to the process or in some other manner, in eachcase in free form or salt form, into a different compound of formula I,separating a mixture of isomers obtainable according to the process andisolating the desired isomer and/or converting a free compound offormula I obtainable according to the process into a salt or a salt of acompound of formula I obtainable according to the process into the freecompound of formula I or into a different salt.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1 or stereoisomer or pharmaceutically acceptable saltthereof, and pharmaceutical excipients.
 14. A method of treatingpathological symptoms of the human body that are brought about bymodulation of the AT₂ -receptor, which comprises administering atherapeutically effective amount of a compound of formula I according toclaim 1, or of a stereoisomer or pharmaceutically acceptable saltthereof.
 15. A method according to claim 14 wherein the pathologicalsymptoms to be treated are cell growth and proliferative disorders. 16.A method according to claim 14 wherein the pathological symptoms to betreated are selected from the group consisting of vascular proliferationdisorders, dysmennorhea, sterility caused by anovulation, ovulationdisorders, dysfunction of the corpus luteum, and missed abortion.